Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety.
Tissue transplantation is indicated for the treatment of various diseases, pathologies, and traumatic injuries. Although thousands of transplants are performed each year, nearly 90,000 individuals in the United States alone find themselves on various transplant wait lists for tissues and organs. Contributing to the shortage of available transplant tissue is the over-arching need for compatibility between the transplant donor and the transplant recipient.
Compatibility of transplant donors and recipients stems primarily from the major histocompatibility complex (MHC), which encodes glycoproteins that are expressed on the cell surface. These glycoproteins, referred to in humans as human leukocyte antigens (HLA), play a central role in the immune system's capacity to distinguish between self and non-self. (Thorsby E et al. (2004) Transplant Proc. 36(2Suppl): 16S-21S). There are three main classifications of HLA molecules, HLA-A, HLA-B, and HLA-DR, a set of which is referred to as a haplotype. (Bradley B (1991) Immunol Lett 29:55-59; and, Schreuder G M et al. (1999) Tissue Antigens, 54:490-437). In humans, one haplotype is inherited from each parent.
Each group of HLA molecules is highly polymorphic. (Turner D (2004) Vox Sang. 87 Suppl1:87-90). As such, there is high variability of HLA expression, even among siblings. (Jeras M (2002) Transpl. Immunol. 10:205-14). This high variability of HLA expression is problematic for transplantation purposes, as any HLA mismatch between the transplant donor and recipient will facilitate rejection of the transplanted tissue. (Petersdorf E W (2004) Curr. Op. Hematol. 11:386-391).
Another problem stemming from HLA mismatching is graft versus host disease (GVHD). GVHD typically arises in instances where the grafted tissue contains immunocompetent cells that can attack the tissues of the transplant host. Bone marrow transplantation (BMT) and hematopoietic stem cell transplantation (HSCT) are particularly problematic in this regard as they typically comprise and can generate immunocompetent cells. (Iwasaki T (2004) Clin. Med. Res. 2:243-252).
BMT and HSCT are indicated for various blood diseases and immune disorders, although HSCT is increasingly the preferred method. However, one of the impediments to the survival and overall health of HSCT patients is GVHD and related complications. (Morishima Y et al. (2002) Blood. 99:4200-4206). HLA compatibility plays an important role in graft failure or survival, and whether the transplant recipient is at risk to develop GVHD. (Davies S M (2000) Blood 96:4096-41002; and, Dickinson A M et al. (2005) Curr. Opin. Immunol. 17:517-525).
To stave off GVHD and rejection of the transplanted tissues, transplant recipients must endure a lifetime of immunosuppressive treatment regimens. Many anti-rejection medications cause severe side effects in the transplant patient, and their immunosuppressive effects can leave the patient vulnerable to opportunistic infections and certain cancers. Thus, a significant advance in tissue transplantation would be to provide a means to inhibit adverse immune responses in the transplant recipient such as GVHD and rejection of the transplanted tissue with less severe side effects and complications than, and without the systemic immunosuppression of traditional methods.